Many chronic diseases are characterized by persistent and unremitting inflammation, injury, tissue remodeling and fibrosis. For instance, in the cohort of progressive renal diseases, which includes diabetic nephropathy, IgA nephropathy and proliferative lupus nephritis, these are histologically characterized by mesangial cell expansion and glomerular as well as tubulointerstitial fibrosis. In this respect, ligands of the platelet-derived growth factor (PDGF) receptor-β are probably the best characterized mediators to date.
PDGFs are the primary mitogens for the cells of the mesenchymal and neuroectodermal origin. The PDGF family is composed of four different polypeptide chains, PDGF-A, B, C and D, which have been shown to form 5 distinct proteins by homo and heterodimerization, PDGF-AA, -AB, -BB, -CC and -DD. PDGFs exert their biological activities by activating two structurally related tyrosine kinase receptors, PDGF-Rα and β, which form homo- and heterodimers (e.g., PDGFRαα, PDGFRαβ, PDGFRββ). PDGF-A activates PDGFRαα, while PDGF-B can activate all three receptor dimers, i.e., PDGF-Rαα, PDGF-Rαβ, PDGF-Rββ. PDGF-AB and PDGF-C activate PDGF-Rαα and PDGF-Rαβ, whereas PDGF-D preferentially activates PDGF-Rββ as reviewed by Trojanowska (2008, Rheumatology 47:v2-v4).
PDGFs have been implicated in a wide variety of human diseases, including, but not limited to, atherosclerosis, restenosis, pulmonary hypertension, retinal vascular disease, organ fibrosis (e.g., cardiac, lung, renal and kidney), rheumatoid arthritis, osteoarthritis, tumorigenesis, and systemic sclerosis (SSc; scleroderma) (see, e.g., Trojanowska, 2008, Rheumatology 47:v2-v4; Andrae et al. 2008 Genes Dev. 22:1276-1312).
More specifically, all four PDGF isoforms, as well as both receptor chains, are expressed in the kidney and increased expression of PDGF in glomerular and/or interstitial locations has been documented in a large variety of renal diseases. In addition, increased expression of PDGF receptors occurs in experimental and human renal diseases. Both PDGF-B and PDGF-D appear to be especially important in human renal diseases. Mesangial cells produce PDGF-B in vitro, and various growth factors induce mesangial proliferation via induction of autocrine or paracrine PDGF-B-chain excretion (Silver et al., 1989, Proc. Natl. Acad. Sci. USA 86:1056-1060; Floege et al., 1991, Clin. Exp. Immunol. 86:334-341). Overexpression of PDGF-B-chain induces mesangial proliferation and matrix expansion (Floege et al., 1993, J. Clin. Invest. 92:2952-2962; Isaka et al., 1993, J. Clin. Invest. 92:2597-2601) and PDGF-B-chain or β-receptor knock-out mice fail to develop a mesangium (Leveen et al., 1994, Genes Dev. 8:1875-1887; Soriano P., 1994, Genes Dev. 8:1888-1896).
Specific inhibition of PDGF-B using antibodies, aptamers, soluble PDGF receptors or PDGF β-receptor tyrosine kinase blockers reduces mesangioproliferative changes, prevents long-term renal scarring and improves renal function in a number of different pre-clinical models (Floege et al., 1999, Am. J. Pathol. 154:169-179; Gilbert et al., 2001, Kidney Int. 59:1324-1332; Nakamura et al., 2001, Kidney Int. 59:2134-2145; Ostendorf et al., 2001, J. Am. Soc. Nephrol. 12:909-918).
Similarly, liver fibrosis is commonly observed after chronic liver injury. The major event in hepatic fibrogenesis is the proliferation of, and collagen production by hepatic stellate cells and myofibroblasts. As is the case for glomerulonephritides, PDGF is strongly mitogenic and causes hepatic stellate cell and myofibroblast chemotaxis (Czochra et al., 2006, J. Hepatol. 45:419-28). In human cirrhotic liver, PDGF-BB and PDGFRβ protein expression is markedly enhanced in comparison with normal liver (Ikura et al., 1997, J. Gastroenterol. 32:496-501). In a cholestatic liver injury model induced by bile duct ligation (BDL) in rats, PDGF-B mRNA expression and PDGF-BB protein production has been observed to be increased in the bile duct segment, biliary epithelial cells, infiltrating macrophages and hepatic stellate cells (Kinnman et al., 2000, Lab. Invest. 80: 697-707; Grappone et al., 1999, J. Hepatol. 31:100-109; Bonner, J C, 2004, Cytokine Growth Factor Rev. 15: 255-273). More recently, antibody inhibition of PDGF-B/PDGF-Rβ receptor binding reduced development of liver fibrosis (Ogawa et al., 2010, Hepatol. Res. 40:1128-1141) demonstrating the role of PDGF-B signaling in liver fibrosis.
PDGF-BB-induced signaling via PDGFRβ strongly promotes hepatic stellate cell proliferation, migration and phenotypic change into myofibroblasts, followed by collagen deposition and fibrogenesis (Kinnman et al., 2001, Lab. Invest. 81:1709-1716; Kinnman et al., 2003, Lab. Invest. 83:163-173). Inhibition of the effects of PDGF-B by antisense, blocking mAbs, dominant-negative soluble PDGFRβ or imatinib (STI571, Gleevec®, Glivec®), an inhibitor of tyrosine kinases including both PDGFRs α and β, reduced hepatic hydroxyproline content as well as mRNA expressions of PDGF-B, PDGFRβ, and collagen type 1 in a BDL induced liver fibrosis model in rats (Ogawa et al., 2010, Hepatol. Res. 40:1128-1141; Kinnman et al., 2000, Lab. Invest. 80: 697-707; Kinnman et al., 2001, Lab. Invest. 81:1709-1716; Kinnman et al., 2003, Lab. Invest. 83: 163-173; Borkham et al., 2004, Biochem. Biophys. Res. Commun. 321:413-423; Borkham et al., 2004, Lab. Invest. 84:766-777; Neef et al., 2006, J. Hepatol. 44:167-175).
Taken together the data observed in pre-clinical fibrosis models, especially renal and liver models, underscores the important potential therapeutic effect mediated by inhibiting PDGF-B/PDGFRβ binding and/or signaling to limit undesirable extracellular matrix deposition and to retain organ function.
In sum, fibrotic diseases and disorders mediated by PDGF-AB and/or PDGF-BB signaling via the interaction of these ligands comprising PDGF-B with the PDGFRβ exact a heavy toll on human mortality and morbidity. Therefore, there is a long-felt need for novel potential therapeutics to treat or ameliorate these diseases/disorders, and the present invention meets this need.